SUMMARY Pulmonary Arterial Hypertension is a lethal disease with devastating impact on thousands of patients and families. Our team has studied this tragic disease for more than 3 decades and the progressive knowledge derived from that work now promises to greatly improve outcomes. Our overall theme is to develop and apply therapies which are directed against mechanisms central to Pulmonary Arterial Hypertension (PAH). Our studies indicate that altered estrogen signalling, and defects in intracellular trafficking and insulin resistance, work independently and in concert to drive the vascular dysfunction characteristic of PAH. Our hypothesis is that focused treatment of the hormonal and metabolic derangements which underlie PAH will improve pulmonary vascular function and patient outcomes. Our renewal program includes 3 Projects and 2 Cores. Project 1 is continued from cycle 1 (Sex Hormones in Pulmonary Arterial Hypertension). It explores exciting avenues derived from understanding the direct contribution of sex hormones to pathogenesis and risk by gender. We expect to confirm that estrogen inhibition with tamoxifen is safe and beneficial in PAH. Project 2 is also continued from cycle 1 (Metabolic Function in Pulmonary Vascular Disease) and emerges from our new understanding of the importance of disordered glucose control, insulin resistance and the metabolic syndrome as contributors to PAH. We expect to confirm that metformin and exercise are safe and beneficial in PAH, and to measure individual patient determinants of response. Project 3 is new (Genomic and Circulating Predictors of PAH response - Leader Anna Hemnes MD) which we developed with the goal to advance precision medicine in PAH, for which we are uniquely positioned. There exists a great unmet need for a scientific basis to tailor the treatment approach for PAH. Our longterm future goal is to optimize PAH therapy by understanding the individual determinants of response, for each of our experimental therapies (tamoxifen, metformin, ACE2) as well as approved agent classes (prostacyclins, endothelin blockers, and phosphodiesterase inhibitors). This is an ideal time to translate our successive progress in understanding PAH mechanisms, because the responsible pathways are targeted by approved drugs (tamoxifen, metformin) or exercise, which are safe and tolerable in humans, and our team is experienced and motivated. Neither the studies nor the interventions can be most effective without considering all aspects of the molecular bases of the disease, which is only possible in a highly interactive program such as that we propose here.